Use of sugar derivatives for the prophylaxis and treatment of virus infections

ABSTRACT

Described are the use of hexopyranose compounds of the formula I ##STR1## for the prophylaxis and treatment of virus infections, and novel pharmaceutical preparations especially suitable for the use in accordance with the invention. 
     The substituents in formula I have the meanings given in the claims.

This application is a continuation of application Ser. No. 07/319,909filed Mar. 3, 1989, now abandoned; which is a continuation ofapplication Ser. No. 06/750,667 filed Jul. 1, 1985, now abandoned; whichis a continuation of Ser. No. 06/640,547 filed Aug. 14, 1984, nowabandoned; which is a continuation of Ser. No. 06/515,006 filed Jul. 18,1983, now abandoned.

The present invention relates to the use of sugar derivatives,especially hexopyranose compounds of the formula I, ##STR2## in whicheach of X¹ and X², independently of the other, represents a group of theformula --O-- or --N(R¹⁴)--, R¹⁴ representing hydrogen or lower alkyl,

each of R¹, R², R¹² and R¹³, independently of one another, represents aradical of the formula Ia

    --(Z.sup.1 --Y.sup.1 --X.sup.3).sub.n --A.sup.1            (Ia)

in which n represents 0 or 1, Z¹ represents carbonyl or thiocarbonyl, Y¹represents unsubstituted or substituted alkylene which may beinterrupted by iminocarbonyl or oxycarbonyl, X³ represents a group ofthe formula --O-- or --N(R¹⁴)--, wherein R¹⁴ has the meaning givenabove, and A¹ represents a radical of the formula Ib, ##STR3## in whichR¹⁵ represents an aliphatic or cycloaliphatic radical having at least 7carbon atoms, or A¹ represents a group of the formula Ic, ##STR4## inwhich R¹⁶ represents hydrogen and R¹⁷ represents 2-hydroxyethyl or1,2-dihydroxyethyl, wherein at least one hydroxy group is esterified oretherified by a radical having at least 7 carbon atoms, or in which eachof R¹⁶ and R¹⁷, independently of the other, represents esterified oretherified hydroxymethyl, the esterifying or etherifying radicals havingat least 7 carbon atoms, or

each of R¹, R², R¹² and R¹³, independently of one another, representshydrogen, acyl other than a radical of the formula Ia in which nrepresents 1, or a radical that can be removed under physiologicalconditions,

each of R³, R⁴, R⁵, R⁷ and R⁸, independently of one another, representshydrogen or lower alkyl,

R⁶ represents hydrogen or lower alkyl that is unsubstituted orsubstituted by a group of the formula Id,

    --E--(Z.sup.2 --Y.sup.2 --X.sup.4).sub.m --A.sup.2         (Id)

in which m represents 0 or 1, E represents a group of the formula --O--,--S-- or --N(R¹⁴)--, R¹⁴ having the meaning given above, Z² representscarbonyl or thiocarbonyl, Y² represents unsubstituted or substitutedalkylene which may be interrupted by iminocarbonyl or oxycarbonyl, X⁴represents a group of the formula --O-- or --N(R¹⁴)--, R¹⁴ having themeaning given above, and A² represents a radical of the formula Ib orIc; or by free or etherified hydroxy or mercapto, by esterified hydroxyor mercapto other than a group of the formula Id, by free amino orsubstituted amino other than a group of the formula Id, by free,esterified or amidated carboxy, by cycloalkyl, by carbocyclic aryl or bynitrogen-containing heteroaryl having 5 or 6 ring members in theheterocyclic ring,

or

R⁵ and R⁶ together represent unsubstituted or substituted 1,3- or1,4-lower alkylene,

each of R⁹ and R¹¹, independently of the other, represents a radical ofthe formula Ie,

    --X.sup.5 --Y.sup.3 --X.sup.6 --A.sup.3                    (Ie)

in which X⁵ represents a group of the formula --O--, --S-- or--N(R¹⁴)--, and X⁶ represents a group of the formula --O-- or--N(R¹⁴)--, in each case R¹⁴ having the meaning given above, Y³represents unsubstituted or substituted alkylene which may beinterrupted by iminocarbonyl or oxycarbonyl, and A³ represents a radicalof the formula Ib or Ic, or free hydroxy or mercapto, etherified hydroxyor mercapto other than a radical of the formula Ie, or free amino orsubstituted amino other than a radical of the formula Ie, and

R¹⁰ represents hydrogen or free, esterified or amidated carboxy,

with the proviso that the compounds of the formula I have at least oneradical A¹, A² or A³, and the use of pharmaceutically acceptable saltsof such compounds for the prophylaxis and (preferably) treatment ofvirus infections in warm-blooded animals, especially and includinghumans, and to novel pharmaceutical preparations that containhexopyranose compounds of the formula I.

By contrast with the treatment of bacterial infections, agents availablefor the prophylaxis and treatment of virus infections are few andinadequate so that to overcome viral diseases it is in almost all casesnecessary that the organism itself has adequate powers of defence.

In accordance with the invention it has surprisingly been found that theabove-mentioned hexopyranose compounds of the formula I and theirpharmaceutically acceptable salts are excellently suitable both for theprophylaxis and treatment of virus infections, as demonstrated, forexample, by animal experiments such as those illustrated in theExamples. In these animal experiments animals, such as mice or guineapigs, are infected by a wide variety of types of virus in a dose that islethal for all or the large majority of untreated (control) animals, forexample LD₈₀₋₉₀, and the course of the infection is observed in theuntreated control animals compared with animals that are treated before,at the same time as, or after the infection, with one of theabove-mentioned hexopyranose compounds or a salt thereof.

These experiments demonstrate that the antiviral action of theabove-mentioned hexopyranose compounds of the formula I and their saltsis not achieved by any hitherto known antiviral substance of anystructure. It is especially remarkable that a prophylactic effect isproduced when hexopyranose compounds of the formula I are administeredfrom just a few days up to a few, for example four, weeks beforeinfection, and a therapeutic effect still occurs on administrationseveral days, for example 1 week, after infection.

Remarkable and hitherto unprecedented is also the broad viral spectrumagainst which the above-mentioned compounds are effective.

The hexopyranose compounds of the formula I can be used especially forthe prophylaxis and treatment of diseases caused by the virusesspecified in detail hereinafter [for nomenclature cf. J. L. Melnick,Prog. med. Virol. 26, 214-232 (1980) and 28, 208-221 (1982)]: DNAviruses with cubic symmetry and naked nucleocapsid, DNA viruses withenveloped virion and also RNA viruses with cubic, and those withhelical, symmetry of the capsid.

Preferably, the compounds of the formula I are used in the case of DNAviruses with enveloped virion and cubic symmetry of the capsid, in thecase of RNA viruses with cubic symmetry of the capsid and naked virion,and in the case of RNA viruses with helical symmetry of the capsid, inwhich the nucleocapsid casing is located at the surface membrane, butalso in the case of Adenoviridae, Poxviridae and Coronaviridae, such as,especially, human coronaviruses.

The compounds of the formula I are used especially in the case ofHerpesviridae, Picornaviridae and myxoviruses, but also in the case ofmastadenoviruses, such as, especially, human adenoviruses, in the caseof Chordopoxvirinae, such as, chiefly, orthopoxviruses, such as,especially, for example, vaccinal viruses, in the case of Reoviridae,chiefly (especially human) rotaviruses, and also in the case ofCaliciviridae and Rhabdoviridae, such as, especially, vesiculoviruses inhumans as well as horses, cows and pigs.

The compounds of the formula I are mainly used in the case ofAlphaherpesvirinae like Varicellaviruses, for example humanvaricellazoster viruses, rhinoviruses, cardioviruses andOrthomyxoviridae, but also in the case of Betaherpesvirinae, such as,especially, human cytomegaloviruses, in the case of aphthoviruses,especially aphthoviruses of cloven-hoofed animals, such as, chiefly,cows, and in the case of Paramyxoviridae, such as, especially,pneumoviruses, for example respiratory syncytial viruses in humans, andsuch as, in addition, morbilliviruses or paramyxoviruses, such asparainfluenza viruses, for example human parainfluenza viruses,including Sendai viruses, as well as in the case of arboviruses orvesiculoviruses, for example vesicular stomatitis viruses.

Above all the compounds of the formula I are used for simplex viruses,for example human herpes simplex viruses of types 1 and 2, and in thecase of human encephalomyocarditis viruses, influenza viruses, such asmainly influenza A and influenza B viruses, and most especially in thecase of the viruses mentioned in the Examples.

The hexopyranose compounds of the formula I can be used in accordancewith the invention by administering them enterally or parenterally,especially together with suitable adjuncts or carriers. Preferably theyare applied to the mucous membrane, for example intranasally, rectally,vaginally or to the conjunctiva of the eye, or orally. The antiviraleffect occurs, however, also if administered in other ways, for examplesubcutaneously, intravenously, intramuscularly or if applied to theskin.

The dosage of the active ingredient depends, inter alia, on the speciesof the warm-blooded animal, the defensive condition of the organism. themode of administration and the nature of the virus. There is noespecially pronounced relationship between dosage and action.

For prophylaxis, a single dose of from approximately 0.01 mg toapproximately 25 mg, preferably from 0.05 to 7 mg, for example 0.5 mg,of active ingredient is administered to a warm-blooded animal ofapproximately 70 kg body weight, for example a human. The prophylacticeffect of this dose lasts for several weeks. If required, for example attimes of increased risk of infection, the administration of this dosecan be repeated.

The therapeutic dose for warm-blooded animals of approximately 70 kgbody weight is between 0.1 mg and 50 mg, preferably between 1 and 10 mg,for example 5 mg, especially when administered orally. The dosage in thecase of topical, especially intranasal, administration is lower by up toa factor of 10. If required, the administration of the hexopyranosecompounds of the formula I can be repeated until there is an improvementin the disease. Normally, however, one administration is adequate.

Preferably, the hexopyranose compounds of the formula I are used inaccordance with the invention in the form of pharmaceutical preparationsthat contain a pharmacologically active amount of the active ingredienttogether with pharmaceutically acceptable carriers that are suitable forenteral, for example oral, or parenteral, administration and may beinorganic or organic, solid or liquid. For example, tablets or gelatincapsules that contain the active ingredient together with diluents, forexample lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/orglycerin, and/or lubricants, for example siliceous earth, talc, stearicacid or salts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol, are used. Tablets may likewise contain binders, forexample magnesium aluminium silicate, starches, such as corn, wheat orrice starch, gelatin, methyl cellulose, sodium carboxymethyl celluloseand/or polyvinylpyrrolidone and, if desired, disintegrators, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescing mixtures, or adsorbents, colouring substances,flavouring substances and sweeteners. Furthermore, the pharmacologicallyactive compounds of the present invention can be used in the form ofparenterally administrable preparations, for example infusion solutions.Such solutions are preferably isotonic aqueous solutions or suspensions,and these, for example in the case of lyophilised preparations thatcontain the active ingredient alone or together with a carrier, forexample mannitol, can be prepared before use. The pharmaceuticalpreparations may be sterilised and/or contain adjuncts, for examplepreservatives, stabilisers, wetting agents and/or emulsifiers,solubilisers, salts for regulating the osmotic pressure and/or buffers.The pharmaceutical preparations in question are produced in a mannerknown per se, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes, and contain fromapproximately 0.001% up to approximately 95% of active ingredient, anactive ingredient content of less than 1% being suitable especially forpreparations that are to be topically administered.

Pharmaceutical preparations for enteral or parenteral administrationthat contain an effective amount, but less than 1% by weight, of ahexopyranose compound of the formula I or a salt thereof together with asignificant amount of a pharmaceutical carrier, are novel and theinvention relates also to these.

The invention relates especially to pharmaceutical preparationscontaining a hexopyranose compound of the formula I that is mentionedbelow as being preferred for the use in accordance with the invention.

The following forms of administration, which have not beenprior-published, of hexopyranose compounds of the formula I areespecially suitable for the use in accordance with the invention:creams, ointments, pastes or a gel with an active ingredient content offrom 0.001% up to, but exclusive of, 1% by weight, principally of from0.001% to 0.9%, especially from 0.01% to 0.1%, for example 0.05%, forexample ointments for intranasal administration, vaginal or rectalsuppositories or lipsticks, aqueous solutions having an activeingredient content of from 0.001% by weight up to, but exclusive of, 1%by weight, principally from 0.001% to 0.9%, especially from 0.05% to0.5%, for example 0.1%, preferably isotonic, sterile and physiologicallytolerable solutions, for example eye drops, preferably in disposablemicro-containers, or sprays for use in the mouth or pharyngeal cavity,or tablets or capsules having an active ingredient content of from 0.1up to, but exclusive of, 1% by weight, for example 0.9%.

The pharmaceutical preparations described in the Examples are especiallysuitable.

Creams are oil-in-water emulsions that contain more than 50% of water.There are used as oily base substances especially fatty alcohols, forexample lauryl, cetyl or stearyl alcohol, fatty acids, for examplepalmitic or stearic acid, liquid to solid waxes, for example isopropylmyristate, wool wax or beeswax, and/or hydrocarbons, for examplepetroleum jelly (petrolatum) or paraffin oil. There come intoconsideration as emulsifiers surface-active substances havingpredominantly hydrophilic properties, such as corresponding non-ionicemulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxide adducts thereof, such as polyglycerin fatty acid esters orpolyoxyethylene sorbitan fatty acid esters (Tweens), alsopolyoxyethylene fatty alcohol ethers or fatty acid esters, orcorresponding ionic emulsifiers, such as alkali metal salts of fattyalcohol sulphates, for example sodium lauryl sulphate, sodium cetylsulphate or sodium stearyl sulphate, which are usually used in thepresence of fatty alcohols, for example cetyl alcohol or stearylalcohol. Additives to the aqueous phase are, inter alia, agents thatreduce the drying out of creams, for example polyalcohols, such asglycerin, sorbitol, propylene glycol and/or polyethylene glycols, andalso preservatives, perfumes etc.

Ointments are water-in-oil emulsions that contain up to 70%, preferablyfrom approximately 20% to approximately 50%, of water or aqueous phase.There come into consideration as fatty phase especially hydrocarbons,for example petroleum jelly, paraffin oil and/or hard paraffins, which,in order to improve the water-binding ability, preferably containsuitable hydroxy compounds, such as fatty alcohols or esters thereof,for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiersare corresponding lipophilic substances, such as sorbitan fatty acidesters (Spans), for example sorbitan oleate and/or sorbitan isostearate.Additives to the aqueous phase are, for example, humectants, such aspolyalcohols, for example glycerin, propylene glycol, sorbitol and/orpolyethylene glycol, as well as preservatives, perfumes etc.

Fatty ointments are anhydrous and contain as the base substanceespecially hydrocarbons, for example paraffin, petroleum jelly and/orliquid paraffins, also natural or partially synthetic fats, for examplecoconut fatty acid triglyceride, or preferably hardened oils, forexample hydrogenated peanut or castor oil, and fatty acid partial estersof glycerin, for example glycerin mono- and di-stearate, as well as, forexample, the fatty alcohols that increase water-absorbing ability,emulsifiers and/or additives mentioned in connection with the ointments.

Pastes are creams and ointments with secretion-absorbing powderconstituents, such as metal oxides, for example titanium oxide or zincoxide, and also talc and/or aluminium silicates, the purpose of which isto bind any moisture or secretions present.

Foams are administered from pressurized containers and are liquidoil-in-water emulsions in aerosol form, halogenated hydrocarbons, suchas chlorofluoro-lower alkanes, for example dichlorodifluoromethane anddichlorotetrafluoroethane, being used as propellants. There are used asoily phase, inter alia, hydrocarbons, for example paraffin oil, fattyalcohols, for example cetyl alcohol, fatty acid esters, for exampleisopropyl myristate, and/or other waxes. There are used as emulsifiers,inter alia, mixtures of those having predominantly hydrophilicproperties, such as polyoxyethylene sorbitan fatty acid esters (Tweens),and those having predominantly lipophilic properties, such as sorbitanfatty acid esters (Spans). In addition there are the customaryadditives, such as preservatives, etc.

Tinctures and solutions usually have an aqueous/ethanolic base substanceto which there are added, inter alia, polyalcohols, for exampleglycerin, glycols and/or polyethylene glycol, as humectants for reducingevaporation, and fat-restoring substances, such as fatty acid esterswith low polyethylene glycols, that is to say lipophilic substancessoluble in aqueous mixture as a replacement for the fatty substancesremoved from the skin by the ethanol, and, if necessary, other adjunctsand additives.

The manufacture of the topically administrable pharmaceuticalpreparations is carried out in a manner known per se, for example bydissolving or suspending the active ingredient in the base substance, orin a portion thereof, if necessary. When processing the activeingredient in the form of a solution, it is usually dissolved in one ofthe two phases before emulsification; when processing in the form of asuspension it is mixed with a portion of the base substance afteremulsification and then added to the remainder of the formulation.

The above terms used for the definition of the compounds of the formulaI have, within the scope of this application, preferably the followingmeanings:

Acyl, for example as R¹, R², R¹² and R¹³, is especially the acyl radicalof an organic carboxylic acid, especially an aliphatic, but also acycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphaticcarboxylic acid, which may have, for example, up to 90 carbon atoms.

Aliphatic carboxylic acids are, inter alia, alkanecarboxylic acids thatare unsubstituted or substituted, for example, by hydroxy or etherifiedor esterified hydroxy, such as lower alkoxy or lower alkanoyloxy, or byunsubstituted or substituted amino, such as lower alkylamino, di-loweralkylamino or acylamino, for example alkanoylamino, and correspondingalkene- or alkyne-carboxylic acids that may have one or more double ortriple bonds. These acids may contain, for example, up to 90 carbonatoms, R² as the radical of an aliphatic carboxylic acid, in the casewhen X¹ represents a group of the formula --N(R¹⁴)--, preferablyrepresenting the acyl radical of an unsubstituted or hydroxy-substitutedlower alkanecarboxylic acid.

Cycloaliphatic carboxylic acids may be monocyclic or polycyclic and as acycloaliphatic radical contain monocyclic or polycyclic cycloalkyl thatis unsubstituted or is substituted, for example by hydroxy, andcorresponding cycloalkenyl.

In cycloaliphatic-aliphatic radicals, the cycloaliphatic moiety and thealiphatic moiety have the meanings given above; such radicals areespecially monocyclic or polycyclic cycloalkyl-lower alkyl.

Aromatic and araliphatic carboxylic acids are, inter alia, benzoic orphenyl-lower alkanecarboxylic acids that are unsubstituted orsubstituted, for example by lower alkyl, hydroxy, lower alkoxy orhalogen.

Groups that can be removed under physiological conditions are especiallyorganic silyl groups, especially aliphatically substituted silyl groups,such as tri-lower alkylsilyl.

Substituents of alkylene, which is represented by the radicals Y¹, Y²and Y³, are, inter alia, hydroxy, esterified or etherified hydroxy, suchas acyloxy, for example lower alkanoyloxy, or lower alkoxy, amino orsubstituted amino, such as lower alkylamino, di-lower alkylamino oracylamino, for example lower alkanoylamino. In an alkylene radical thatis interrupted by iminocarbonyl or oxycarbonyl, there may be one ormore, for example two, such groups and these may be present as groups ofthe formula --N(R¹⁴)--C(═O)-- or --O--C(═O)--, and as groups of theformula --C(═O)--N(R¹⁴)-- or --C(═O)--O--, and R¹⁴ has the meaning givenabove and preferably represents hydrogen. An alkylene radical formed bythe groups R⁵ and R⁶ and having 3 or 4 carbon atoms in the chain may besubstituted, for example by hydroxy, which may be acylated, for exampleby a group of the formula Ia.

An aliphatic radical having at least 7 carbon atoms that is the groupR¹⁵ or etherifies a hydroxy group in a radical R¹⁶ or R¹⁷ is especiallya corresponding unsubstituted or substituted alkyl radical but may alsorepresent a corresponding unsaturated radical, such as an unsubstitutedor substituted alkenyl radical having one or more double bonds, suchradicals having, for example, from 7 up to and including 90 carbonatoms, preferably from 7 up to and including 30 carbon atoms.Substituents of such aliphatic radicals are, for example, hydroxy,etherified or esterified hydroxy, such as lower alkoxy or loweralkanoyloxy and-or unsubstituted or substituted amino, such as loweralkylamino, di-lower alkylamino or alkanoylamino.

A corresponding cycloaliphatic radical that is the group R¹⁵ or aradical etherifying a hydroxy group in a radical R¹⁶ or R¹⁷ isespecially monocyclic or polycyclic cycloalkyl, or also correspondingcycloalkenyl, which may contain one or more double bonds. Such radicalscontain at least 7, and preferably from 7 to 30, carbon atoms, and may,in addition, be substituted, for example by hydroxy, etherified oresterified hydroxy, such as lower alkoxy or lower alkanoyloxy, or byunsubstituted or substituted amino, such as lower alkylamino, di-loweralkylamino or alkanoylamino.

Etherified hydroxy or substituted amino as a radical R⁹ or R¹¹ is, forexample, lower alkoxy, or, for example, lower alkylamino, in which loweralkyl may be substituted.

A radical esterifying a hydroxy group in a radical R¹⁶ or R¹⁷ isespecially an acyl radical of an organic carboxylic acid, especially ofone of the above-mentioned aliphatic and cycloaliphatic,cycloaliphaticaliphatic, aromatic or araliphatic, carboxylic acids,preferably having from 7 to 90 carbon atoms.

Etherified hydroxy or mercapto or esterified hydroxy or mercapto otherthan a radical of the formula Id as substituent of lower alkyl R⁶ is,for example, lower alkoxy, acyloxy, such as alkanoyloxy, whereinalkanoyl contains up to 90, for example from 7 to 30, carbon atoms andmay optionally be substituted, for example by hydroxy, or is halogen,lower alkylthio or acylthio, such as alkanoylthio, wherein alkanoylcontains up to 90, for example from 7 to 30, carbon atoms. Substitutedamino other than a radical of the formula Id as substituent of a loweralkyl group R⁶ is, for example, lower alkylamino, guanylamino oracylamino, such as alkanoylamino, wherein alkanoyl may contain up to 90,for example up to 30, carbon atoms. Esterified carboxy as substituent ofa lower alkyl radical R⁶ is preferably carboxy esterified by analiphatic radical, such as alkyl having up to 30 carbon atoms, that isto say, for example, corresponding alkoxycarbonyl, whilst correspondingamidated carboxy, is, for example, aminocarbonyl or loweralkylaminocarbonyl, wherein lower alkyl may be substituted, for exampleby carboxy, alkoxycarbonyl or aminocarbonyl. Esterified or amidatedcarboxy in a radical R⁶ may also be a radical of the formula ##STR5## inwhich m, E, Y², X⁴ and A² have the meanings given above.

Aryl as substituent of a lower alkyl group R⁶ is especially phenyl thatis unsubstituted or substituted, for example by lower alkyl, hydroxy oretherified or esterified hydroxy, such as lower alkoxy, or halogen,whilst nitrogen-containing heteroaryl having 5 or 6 ring members in theheterocyclic ring as corresponding substituent of R⁶ is monocyclic orbicyclic heteroaryl containing one or two nitrogen atoms as ringmembers.

Etherified mercapto as radical R⁹ or R¹¹ is especially lower alkylthio,whilst in a lower alkylamino radical R⁹ or R¹¹ the lower alkyl group maybe substituted, for example by carboxy, lower alkoxycarbonyl oraminocarbonyl.

Esterified carboxy R¹⁰ is especially lower alkoxycarbonyl, whilstamidated carboxyl R¹⁰ may be carbamoyl or N-lower alkylcarbamoyl,wherein lower alkyl may be substituted, for example by carboxy, loweralkoxycarbonyl or aminocarbonyl.

In the context of the present description, the general terms used abovehave the following meanings, radicals and compounds that are termed"lower" containing up to and including 7, preferably up to and including4, carbon atoms:

Alkyl is, for example, lower alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tributyl, sec.-butyl or tert.-butyl, also n-pentyl,neopentyl, n-hexyl or n-heptyl, or higher alkyl, such as straight-chainor branched octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, nonadecyl or heneicosyl, and alsohigher alkyl of the triacontyl, tetracontyl, pentacontyl, hexacontyl,heptacontyl, octacontyl or nonacontyl series.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy or tert.-butoxy.

Alkanoyloxy is lower or higher alkanoyloxy, lower alkanoyloxy being, forexample, formyloxy, acetoxy, propionyloxy or butyryloxy, whilst higheralkanoyloxy is, for example, lauroyloxy, myristinoyloxy, palmitoyloxy,stearoyloxy or behenoyloxy. Alkanoyloxy substituted by hydroxy, forexample higher alkanoyloxy, is, inter alia, mycoloyloxy.

Lower alkylamino is, for example, methylamino, ethylamino, n-propylaminoor isopropylamino. Di-lower alkylamino is, for example, dimethylamino,diethylamino or di-isopropylamino. Alkanoylamino is lower alkanoylamino,for example formylamino, acetylamino or propionylamino, or higheralkanoylamino, for example lauroylamino, palmitoylamino, stearoylaminoor behenoylamino.

An alkanecarboxylic acid is, for example, a lower alkanecarboxylic acid,such as acetic acid, propionic acid, butyric acid or caproic acid, or ahigher alkanecarboxylic acid, such as lauric acid, myristic acid,palmitic acid, stearic acid or behenic acid, whilst, for example, analkanoic acid substituted by hydroxy may be, inter alia, mycolic acid.

Alkene- and alkyne-carboxylic acids are, inter alia, lower alkene- andlower alkyne-carboxylic acids, such as acrylic acid, crotonic acid ortetrolic acid, or higher alkene- and higher alkyne-carboxylic acids,such as undecylenic acid, oleic acid or elaidic acid. The acyl radicalof a lower alkanecarboxylic acid, which is the group R² in the case whenX¹ represents the radical of the formula --N(R¹⁴)--, is especiallyacetyl or hydroxyacetyl, and propionyl.

Cycloalkyl is, for example, cyclopentyl, cyclohexyl or adamantyl, whilstcycloalkenyl may be, for example, 1-cyclohexenyl, and cycloalkyl-loweralkyl may be, for example, 3-cholanylmethyl or the acyl radical ofcholanic acid.

Phenyl-lower alkanecarboxylic acids are, for example, phenylacetic acidor phenylpropionic acid, which may be substituted, for example asstated.

Halogen is preferably halogen having an atomic number of up to 35 andrepresents especially chlorine, but also fluorine or bromine.

Tri-lower alkylsilyl is especially trimethylsilyl.

Alkylene is straight-chain or branched and is especially lower alkylene,for example methylene, ethylene, 1,2-propylene, 1,3-propylene or1,6-hexylene, but also higher alkylene, such as 1,11-undecylene.

Alkenyl is lower alkenyl, for example allyl or methallyl, or higheralkenyl, for example decenyl.

Lower alkylthio is, for example, methylthio or ethylthio.

In an alkanoylthio radical, the alkanoyl radical represents loweralkanoyl, for example acetyl, propionyl, butyryl or hexanoyl, but mayalso represent higher alkanoyl, for example lauroyl, myristinoyl,palmitoyl, stearoyl or behenoyl.

Alkoxycarbonyl is lower alkoxycarbonyl, for example methoxycarbonyl,ethoxycarbonyl or tert.-butoxycarbonyl, or higher alkoxycarbonyl, forexample dodecyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonylor heneicosyloxycarbonyl.

Lower alkylaminocarbonyl is, for example, methylaminocarbonyl orethylaminocarbonyl, also carboxy-, lower alkoxycarbonyl- orcarbamoyl-lower alkylaminocarbonyl, such as carboxymethylaminocarbonyl,1-carboxyethylaminocarbonyl, methoxycarbonylmethylaminocarbonyl orcarbamoylmethylaminocarbonyl.

Nitrogen-containing heteroaryl having 5 or 6 ring members in theheterocyclic ring is, for example, imidazolyl, such as 4-imidazolyl, orindolyl, such as 3-indolyl.

The hexopyranose compounds of the formula I may be in the form ofisomeric mixtures or pure isomers.

They may thus have the L- or DL-configuration in the sugar moiety, buthave preferably the D-configuration. Furthermore, the hexopyranosemoiety may be that of any hexose, but is preferably that of an allose,galactose or mannose, but especially of a glucose. That is to say, thecompounds of the present invention are especially corresponding allo-,galacto- or mannopyranose compounds, but more especially correspondingglucopyranose compounds, having preferably the D-configuration.

The radical of the formula --C(R³)(R⁴)--C(═O)-- linked to the oxygenatom, in the case where one of the groups R³ and R⁴ is other thanhydrogen, is preferably in optically active form and has especially theD-configuration, whilst the radical of the amino acid of the formula--N(R⁵)--C(R⁶)(R⁷)--C(═O)--, in the case where one of the radicals R⁶and R⁷ is other than hydrogen, is likewise preferably in opticallyactive form, especially in the L-configuration, and the terminalα-aminoglutaric acid radical is preferably in optically active form,especially in the D-configuration. Furthermore, the optionallysubstituted 1-hydroxy group of the formula --O--R¹ may have the α- orthe β-configuration; the novel compounds of the formula I may, however,also be in the form of a mixture of the 1-α-and 1-β-isomers.

In the compounds of the formula I, the proton bonded to phosphorus viaan oxygen atom can readily be replaced by a cation, that is to say, thecompounds form salts. In this case, the compounds of the formula I maybe in salt form or in the form of a mixture of the free compounds andtheir salts. These are especially metal or ammonium salts, such asalkali metal and alkaline earth metal salts, for example sodium,potassium, magnesium or calcium salts, and ammonium salts, or salts withsuitable organic amines, such as lower alkylamines, for exampletriethylamine. Compounds of the formula I having basic groups, forexample amino groups, are in the form of internal salts but, when thereare more basic than acidic groups in a molecule of the formula I, theymay also form acid addition salts with external acids, such as saltswith inorganic acids, such as mineral acids, for example hydrochloric,sulphuric or phosphoric acid, or organic carboxylic or sulphonic acids,for example acetic, maleic, fumaric, tartaric, citric, methanesulphonicor 4-toluenesulphonic acid. Only the pharmaceutically acceptable,non-toxic salts are used therapeutically.

The above-mentioned hexopyranose compounds of the formula I and theirsalts and their preparation are described in the European PatentApplications with the publication numbers 0025 495, 0027 258 and 0056992, which are in the name of the assignee of the present invention, andthe last-mentioned Application was not published until after thepriority data of the present Application. The use in accordance with theinvention of the phosphorylmuramyl peptides per se for the prophylaxisand treatment of virus infections is neither described in, nor madeobvious by, the above-mentioned Applications. The penultimate paragraphon page 13 of the above-mentioned application 0025 495 relates merely totheir use as adjuvant in admixture with vaccines.

The present invention relates especially to the use of:

(a) compounds of the formula I in which X¹ and X² have the meaningsgiven above, R¹ represents a radical of the formula Ia in which n, Z¹,Y¹, X³ and A¹ have the meanings given above, each of R², R¹² and R¹³,independently of one another, represents hydrogen, acyl other than aradical of the formula Ia in which n represents 1, or a group that canbe removed under physiological conditions, R³, R⁴, R⁵, R⁷, R⁸ and R¹⁰have the meanings given above, R⁶ represents hydrogen or lower alkylthat is unsubstituted or substituted by free or etherified hydroxy ormercapto, by esterified hydroxy or mercapto other than a correspondinggroup of the formula Id or by free amino or substituted amino other thana corresponding group of the formula Id, by free, esterified or amidatedcarboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containingheteroaryl having 5 or 6 ring members in the heterocyclic ring, or R⁵and R⁶ together represent unsubstituted or substituted 1,3- or 1,4-loweralkylene, and in which each of R⁹ and R¹¹, independently of the other,represents free hydroxy or mercapto, etherified hydroxy or mercaptoother than a radical of the formula Ie, or free amino or substitutedamino other than a radical of the formula Ie, it being possible for freefunctional groups to be in protected form, and of pharmaceuticallyacceptable salts of such compounds;

(b) compounds of the formula I in which X¹ and X² have the meaningsgiven above, R² represents a radical of the formula Ia in which n, Z¹,Y¹, X³ and A¹ have the meanings given above, each of R¹, R¹² and R¹³,independently of one another, represents hydrogen, acyl other than aradical of the formula Ia in which n represents 1, or a group that canbe removed under physiological conditions, R³, R⁴, R⁵, R⁷, R⁸ and R¹⁰have the meanings given above, R⁶ represents hydrogen or lower alkylthat is unsubstituted or substituted by free or etherified hydroxy ormercapto, by esterified hydroxy or mercapto other than a correspondinggroup of the formula Id, by free amino or substituted amino other than acorresponding group of the formula Id, by free, esterified or amidatedcarboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containingheteroaryl having 5 or 6 ring members in the heterocyclic ring, or R⁵and R⁶ together represent unsubstituted or substituted 1,3- or 1,4-loweralkylene, and in which each of R⁹ and R¹¹, independently of the other,represents free hydroxy or mercapto, etherified hydroxy or mercaptoother than a radical of the formula Ie, or free amino or substitutedamino other than a radical of the formula Ie, it being possible for freefunctional groups to be in protected form, and of pharmaceuticallyacceptable salts of such compounds;

(c) compounds of the formula I in which X¹ and X² have the meaningsgiven above, R¹³ represents a radical of the formula Ia in which n, Z¹,Y¹, X³ and A¹ have the meanings given above, each of R¹, R² and R¹²,independently of one another, represents hydrogen, acyl other than aradical of the formula Ia in which n represents 1, or a group that canbe removed under physiological conditions, R³, R⁴, R⁵, R⁷, R⁸ and R¹⁰have the meanings given above, R⁶ represents hydrogen or lower alkylthat is unsubstituted or substituted by free or etherified hydroxy ormercapto, by esterified hydroxy or mercapto other than a correspondinggroup of the formula Id, by free amino or substituted amino other than acorresponding group of the formula Id, by free, esterified or amidatedcarboxy, by cycloalkyl, by carbocyclic aryl or by nitrogen-containingheteroaryl having 5 or 6 ring members in the heterocyclic ring, orR.sup. 5 and R⁶ together represent unsubstituted or substituted loweralkylene having 3 or 4 carbon atoms in the chain, and in which each ofR⁹ and R¹¹, independently of the other, represents free hydroxy ormercapto, etherified hydroxy or mercapto other than a radical of theformula Ie, or free amino or substituted amino other than a radical ofthe formula Ie, it being possible for free functional groups to be inprotected form, and of pharmaceutically acceptable salts of suchcompounds; or

(d) compounds of the formula I in which X¹ and X² have the meaningsgiven above, each of R¹, R², R¹² and R¹³, independently of one another,represents hydrogen, acyl other than a radical of the formula Ia inwhich n represents 1, or a group that can be removed under physiologicalconditions, R³, R⁴, R⁵, R⁷, R⁸ and R¹⁰ have the meanings given above, R⁶represents lower alkyl substituted by a radical of the formula Id, inwhich m, E, Z², Y², X⁴ and A² have the meanings given above, or R⁶represents lower alkyl substituted by a group of the formula Ida inwhich m, E, Y², X⁴ and A² have the meanings given above, and in whicheach of R⁹ and R¹¹, independently of the other, represents free hydroxyor mercapto, etherified hydroxy or mercapto other than a radical of theformula Ie, or free amino or substituted amino other than a radical ofthe formula Ie, it being possible for free functional groups to be inprotected form, and of pharmaceutically acceptable salts of suchcompounds, and to novel pharmaceutical preparations containing thesecompounds.

The invention includes especially the use of hexopyranose compounds,particularly D-glucopyranose compounds of the formula I, in which X¹ andX² have the meanings given above, each of R¹, R², R¹² and R¹³,independently of one another, represents hydrogen, the acyl radical ofan aliphatic, cycloaliphatic, aromatic or araliphatic carboxylic acid,especially of an alkanecarboxylic acid having up to 90 carbon atoms thatis unsubstituted or substituted, for example by hydroxy, amino and/oralkanoylamino, such as higher alkanoylamino, a tri-lower alkylsilylgroup or a radical of the formula Ia in which n and X³ have the meaningsgiven above, Z¹ represents thiocarbonyl or, preferably, carbonyl, Y¹represents lower alkylene which may be interrupted by iminocarbonyl oroxycarbonyl, and A¹ represents a radical of the formula Ib or Ic, inwhich R¹⁵ represents an aliphatic radical having at least 7 carbonatoms, R¹⁶ represents hydrogen and R¹⁷ represents 2-hydroxyethyl or1,2-dihydroxyethyl, in which at least one hydroxy group is etherified byan aliphatic radical having at least 7 and up to 90 carbon atoms or isesterified by a corresponding aliphatic acyl radical, or each of R¹⁶ andR¹⁷, independently of the other, represents hydroxymethyl etherified byan aliphatic radical having at least 7 and up to 90 carbon atoms oresterified by a corresponding aliphatic acyl radical, R³, R⁴, R⁵, R⁷ andR⁸ have the meanings given above, R⁶ represents hydrogen or lower alkylwhich is unsubstituted or substituted by a radical of the formula Id inwhich m, E and X⁴ have the meanings given above, Z² representsthiocarbonyl or, especially, carbonyl, Y² represents lower alkylenewhich may be interrupted by iminocarbonyl or oxycarbonyl, and A²represents a radical of the formula Ib or Ic in which R¹⁵ represents analiphatic radical having at least 7 carbon atoms, R¹⁶ representshydrogen and R¹⁷ represents 2-hydroxyethyl or 1,2-dihydroxyethyl, inwhich at least one hydroxy group is esterified by an aliphatic radicalhaving at least 7 and up to 90 carbon atoms or by a correspondingaliphatic acyl radical, or each of R¹⁶ and R¹⁷, independently of theother, represents hydroxymethyl etherified by an aliphatic radicalhaving at least 7 and up to 90 carbon atoms or esterified by acorresponding aliphatic acyl radical, or R⁶ represents lower alkylsubstituted by hydroxy or mercapto, by hydroxy or mercapto etherified byan aliphatic radical containing up to 90 carbon atoms, by hydroxy ormercapto that is esterified by an aliphatic acyl radical containing upto 90 carbon atoms and is other than the group of the formula Id, byamino, by amino that is substituted by an acyl radical containing up to90 carbon atoms and is other than a radical of the formula Id, by freecarboxy, by lower alkoxycarbonyl, by carbamoyl, by loweralkylaminocarbonyl, by carboxy-lower alkylaminocarbonyl or by amidatedcarboxyl of the formula Ida, by phenyl that is unsubstituted orsubstituted by hydroxy, lower alkoxy or halogen, or by imidazolyl orindolyl, or R⁵ and R⁶ together represent 1,3- or 1,4-lower alkylene,each of R⁹ and R¹¹, independently of the other, represents hydroxy,lower alkoxy, amino, lower alkylamino, carboxy-lower alkylamino, or aradical of the formula Ie, in which X⁵ and X⁶ have the meanings givenabove, Y³ represents lower alkylene which may be interrupted byiminocarbonyl or oxycarbonyl, and A³ represents a radical of the formulaIb or Ic, in which R¹⁵ represents an aliphatic radical having at least 7carbon atoms, R¹⁶ represents hydrogen and R¹⁷ represents 2-hydroxyethylor 1,2-dihydroxyethyl, in which at least one hydroxy group is etherifiedby an aliphatic radical having at least 7 and up to 90 carbon atoms oris esterified by a corresponding aliphatic acyl radical, or each of R¹⁶and R¹⁷, independently of the other, represents hydroxymethyl etherifiedby an aliphatic radical having at least 7 and up to 90 carbon atoms oresterified by a corresponding aliphatic acyl radical, and R¹⁰ representshydrogen, carboxy, lower alkoxycarbonyl, carbamoyl, loweralkylaminocarbonyl or carboxy-lower alkylaminocarbonyl, it beingpossible for free functional groups to be in protected form, with theproviso that the compounds of the formula I have at least one radicalA¹, A² or A³, and of pharmaceutically acceptable salts of suchcompounds, and to novel pharmaceutical preparations containing thesecompounds.

The invention relates especially to (e) the use of the hexapyranosecompounds mentioned under (a), (b), (c) and (d), especiallyD-glucopyranose compounds of the formula I in which one, several or allof the radicals X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹² and R¹³ have the meanings given in the preceding paragraphs, and ofpharmaceutically acceptable salts of such compounds.

The invention relates more especially to (f) the use of D-glucopyranosecompounds of the formula If ##STR6## in which R_(a) ¹ representshydrogen, lower alkanoyl or a group of the formula Ia in which nrepresents 1, Z¹ represents carbonyl, Y¹ represents lower alkylene whichmay be interrupted by iminocarbonyl, X³ represents a group of theformula --O-- or --NH--, and A¹ represents a radical of the formula Ibor Ic, in which R¹⁵ represents an alkyl radical having from 7 to 30carbon atoms that is unsubstituted or substituted by hydroxy, aminoand/or alkanoylamino having up to 30 carbon atoms, R¹⁶ representshydrogen and R¹⁷ represents 2-hydroxyethyl or 1,2-dihydroxyethyl, thehydroxy groups in a radical R¹⁷ being etherified by an alkyl radicalhaving from 7 to 30 carbon atoms that is unsubstituted or substituted byhydroxy, amino and/or alkanoylamino having up to 30 carbon atoms orbeing esterified by an alkanoyl radical having from 7 to 90 carbon atomsthat is unsubstituted or substituted by hydroxy, amino and/oralkanoylamino having up to 30 carbon atoms, or each of R¹⁶ and R¹⁷,independently of the other, represents hydroxymethyl in which thehydroxy group is etherified by an alkyl radical having from 7 to 30carbon atoms that is unsubstituted or substituted by hydroxy, aminoand/or alkanoylamino having up to 30 carbon atoms or is esterified by analkanoyl radical having from 7 to 90 carbon atoms that is unsubstitutedor substituted by hydroxy, amino and/or alkanoylamino having up to 30carbon atoms, R_(a) ² represents lower alkanoyl, hydroxy-lower alkanoyl,benzoyl or a group of the formula Ia, in which n, Z¹, Y¹, X³ and A¹ havethe meanings given above, R_(a) ¹² represents hydrogen or loweralkanoyl, R_(a) ¹³ represents hydrogen, alkanoyl or hydroxyalkanoylhaving up to 90 carbon atoms, alkanoylaminoalkanoyl having up to 30carbon atoms or a group of the formula Ia in which n, Z¹, Y¹, X³ and A¹have the meanings given above, R_(a) ³ and R_(a) ⁷ represent hydrogen ormethyl, R_(a) ⁶ represents hydrogen or lower alkyl that is unsubstitutedor substituted by free hydroxy or mercapto, lower alkoxy, loweralkylthio, alkanoyloxy or hydroxyalkanoyloxy having up to 90 carbonatoms, phenyl, imidazolyl, indolyl or by a group of the formula Id, inwhich m represents 1, E represents a group of the formula --O-- or--S--, Z² represents carbonyl, Y² represents lower alkylene which may beinterrupted by iminocarbonyl, X⁴ represents a group of the formula--O--, and A² represents a radical of the formula Ib or Ic, in which R¹⁵represents an alkyl radical having from 7 to 30 carbon atoms that isunsubstituted or substituted by hydroxy, amino and/or alkanoylaminohaving up to 30 carbon atoms, R¹⁶ represents hydrogen and R¹⁷ represents2-hydroxyethyl or 1,2-dihydroxyethyl, the hydroxy groups in a radicalR¹⁷ being etherified by an alkyl radical having from 7 to 30 carbonatoms that is unsubstituted or substituted by hydroxy, amino and/oralkanoylamino having up to 30 carbon atoms or being esterified by analkanoyl radical having from 7 to 90 carbon atoms that is unsubstitutedor substituted by hydroxy, amino and/or alkanoylamino having up to 30carbon atoms, or each of R¹⁶ and R¹⁷, independently of the other,represents hydroxymethyl in which the hydroxy group is etherified by analkyl radical having from 7 to 30 carbon atoms that is unsubstituted orsubstituted by hydroxy, amino and/or alkanoylamino having up to 30carbon atoms, or is esterified by an alkanoyl radical having from 7 to90 carbon atoms that is unsubstituted or substituted by hydroxy, aminoand/or alkanoylamino having up to 30 carbon atoms, and each of theradicals R_(a) ⁹ and R_(a) ¹¹, independently of the other, representshydroxy, lower alkoxy, amino, lower alkylamino, carboxy-lower alkylaminoor a radical of the formula Ie in which X⁵ represents a group of theformula --O-- or --NH--, Y³ represents lower alkylene which may beinterrupted by iminocarbonyl, X⁶ represents a group of the formula--O--, and A₃ represents a radical of the formula Ib or Ic, in which R¹⁵represents an alkyl radical having from 7 to 30 carbon atoms that isunsubstituted or substituted by hydroxy, amino and/or alkanoylaminohaving up to 30 carbon atoms, R¹⁶ represents hydrogen and R¹⁷ represents2-hydroxyethyl or 1,2-dihydroxyethyl, the hydroxy groups in a radicalR¹⁷ being etherified by an alkyl radical having from 7 to 30 carbonatoms that is unsubstituted or substituted by hydroxy, amino and/oralkanoylamino having up to 30 carbon atoms, or being esterified by analkanoyl radical having from 7 to 90 carbon atoms that is unsubstitutedor substituted by hydroxy, amino and/or alkanoylamino having up to 30carbon atoms, or each of R¹⁶ and R¹⁷, independently of the other,represents hydroxymethyl in which the hydroxy group is etherified by analkyl radical having from 7 to 30 carbon atoms that is unsubstituted orsubstituted by hydroxy, amino and/or alkanoylamino having up to 30carbon atoms, or is esterified by an alkanoyl radical having from 7 to90 carbon atoms that is unsubstituted or substituted by hydroxy, aminoand/or alkanoylamino having up to 30 carbon atoms, R_(a) ⁹ preferablyrepresents one of the amino groups and R.sub. a¹¹ preferably representshydroxy, with the proviso that the compounds have at least one, andpreferably only one, radical A¹, A² or A³, and of pharmaceuticallyacceptable salts thereof, and to novel pharmaceutical preparationscontaining these compounds,

The invention relates especially to (g) the use of the D-glucopyranosecompounds of the formula I mentioned under (a), (b), (c) and (d) inwhich X¹ represents a group of the formula --NH--, X² represents a groupof the formula --O--, R⁴, R⁵, R⁸ and R¹⁰ represent hydrogen, and R¹, R²,R³, R⁶, R⁷, R⁹, R¹¹, R¹² and R¹³ have the meanings given in theforegoing section for the radicals R_(a) ¹, R_(a) ², R_(a) ³, R_(a) ⁶,R_(a) ⁷, R_(a) ⁹, R_(a) ¹¹, R_(a) ¹² and R_(a) ¹³, respectively, and ofpharmaceutically acceptable salts thereof.

The invention relates chiefly to h) the use of compounds of the formulaI in which X¹ represents a group of the formula --N(R¹⁴)--, R¹⁴representing hydrogen or C₁₋₄ -alkyl, X² represents oxygen, R¹represents hydrogen, lower alkanoyl, or a group of the formula Ia inwhich n represents 0 or 1, Z¹ represents carbonyl, Y¹ represents loweralkylene which may be interrupted by iminocarbonyl, X³ represents oxygenand A¹ represents a radical of the formula Ib or Ic in which R¹⁵represents an alkyl or alkenyl radical having from 7 to 30 carbon atomsthat is unsubstituted or substituted by hydroxy, amino and/oralkanoylamino having up to 22 carbon atoms, R¹⁶ represents hydrogen andR¹⁷ represents 2-hydroxyethyl or 1,2-dihydroxyethyl, at least onehydroxy group in a radical R¹⁷ being etherified by an alkyl or alkenylradical having from 7 to 30 carbon atoms, or being esterified by analkanoyl or alkenoyl radical having from 7 to 30 carbon atoms, or eachof R¹⁶ and R.sup. 17, independently of the other, representshydroxymethyl in which the hydroxy group is etherified by an alkyl oralkenyl radical having from 7 to 30 carbon atoms, or is esterified by analkanoyl or alkenoyl radical having from 7 to 30 carbon atoms, R²represents lower alkanoyl, hydroxy-lower alkanoyl, benzoyl or,independently of R¹, R¹² and R¹³, a group of the formula Ia as definedhereinbefore, each of R³, R⁴, R⁵, R⁷ and R⁸, independently of oneanother, represents hydrogen, methyl or ethyl, R⁶ represents hydrogen,or lower alkyl that is unsubstituted or substituted by free hydroxy,free mercapto, lower alkoxy, lower alkylthio, alkanoyloxy having from 2to 30 carbon atoms, alkenoyloxy having from 6 to 30 carbon atoms,phenyl, 4-hydroxyphenyl, or by a group of the formula Id in which mrepresents 0 or 1, E represents oxygen or sulphur, Z² representscarbonyl, Y² represents lower alkylene that is unsubstituted orsubstituted by phenyl and may be interrupted by iminocarbonyl, X⁴represents oxygen and A², independently of A¹ and A³, represents aradical of the formula Ib or Ic as defined hereinbefore in thisSpecification, each of R⁹ and R¹¹, independently of the other,represents hydroxy, lower alkoxy, amino, lower alkylamino, carboxy-loweralkylamino, lower alkoxycarbonyl-lower alkylamino, carbamoyl-loweralkylamino, or a radical of the formula Ie in which X⁵ represents oxygenor NH, Y³ represents lower alkylene which may be interrupted byiminocarbonyl, X⁶ represents oxygen and A³, independently of A¹ and A²,represents a radical of the formula Ib or Ic as defined hereinbefore inthis Specification, R¹⁰ represents hydrogen, R¹² represents hydrogen,lower alkanoyl or the same radical as R¹³, and R¹³ represents hydrogen,or alkanoyl or alkenoyl each having up to 30 carbon atoms or,independently of R¹ and R², a radical of the formula Ia as definedhereinbefore in this Specification, with the proviso that the compoundscontain at least one, and at most two, radicals selected from the groupA¹ , A² and A³, and the use of pharmaceutically acceptable salts ofthese compounds.

The invention relates especially to i) the use of compounds of theformula I in which X¹ represents the group NH, X² represents oxygen, R¹represents hydrogen or lower alkanoyl, R² represents lower alkanoyl,benzoyl or a group of the formula Ia in which n represents 0 or 1, Z¹represents carbonyl, Y¹ represents lower alkylene which may beinterrupted by one or two iminocarbonyl groups, X³ represents oxygen,and A¹ represents a radical of the formula Ib or Ic in which R¹⁵represents an alkyl radical having from 7 to 22 carbon atoms, R¹⁶represents hydrogen, and R¹⁷ represents 1,2-dihydroxyethyl in which eachof the hydroxy groups, independently of the other, is esterified by analkanoyl or alkenoyl radical having from 10 to 22 carbon atoms, R³represents hydrogen or methyl, R⁴, R⁵, R⁷ and R⁸ each representshydrogen, R⁶ represents hydrogen, or lower alkyl that is unsubstitutedor substituted by free hydroxy, alkanoyloxy having from 2 to 22 carbonatoms, alkenoyloxy having from 6 to 22 carbon atoms, phenyl or by agroup of the formula Id in which m represents 0 or 1, E representsoxygen, Z² represents carbonyl, Y² represents lower alkylene that isunsubstituted or substituted by phenyl and may be interrupted byiminocarbonyl, X⁴ represents oxygen and A², independently of A¹ and A³,represents a radical of the above-defined formula Ib or Ic, each of R⁹and R¹¹, independently of the other, represents hydroxy, lower alkoxy,amino, lower alkylamino, α-carboxy-lower alkylamino, α-loweralkoxycarbonyl-lower alkylamino, α-carbamoyl-lower alkylamino, or aradical of the formula Ie in which X⁵ represents the group NH, Y³represents lower alkylene which may be interrupted by one or twoiminocarbonyl groups, X⁶ represents oxygen and A³, independently of A¹and A², represents a radical of the formula Ib or Ic definedhereinbefore, R¹⁰ represents hydrogen, R¹² represents hydrogen, loweralkanoyl or the same radical as R¹³, and R¹³ represents hydrogen,alkanoyl having from 2 to 22 carbon atoms, alkenoyl having from 6 to 22carbon atoms or, independently of R², a radical of the formula Ia asdefined hereinbefore, and the use of pharmaceutically acceptable saltsof these compounds.

The invention relates most especially to j) the use of compounds of theformula I in which X¹ represents the group NH, X² represents oxygen, R¹represents hydrogen or C₂₋₄ -alkanoyl, R² represents C₂₋₄ -alkanoyl or agroup of the formula Ia in which n represents 0 or 1, Z¹ representscarbonyl, Y¹ represents lower alkylene which may be interrupted by oneor two iminocarbonyl groups, X³ represents oxygen, and A¹ represents aradical of the formula Ib or Ic in which R¹⁵ represents an unbranchedalkyl radical having from 12 to 18 carbon atoms, R¹⁶ represents hydrogenand R¹⁷ represents 1,2-dipalmitoyloxyethyl or2-oleoyloxy-1-palmitoyloxyethyl, R³ represents hydrogen or methyl, R⁴,R⁵, R⁷, R⁸ and R¹⁰ each represents hydrogen, R⁶ represents methyl, ethylor isopropyl, each of which is unsubstituted or substituted by a radicalof the formula Id in which m represents 0 or 1, E represents oxygen, Z²represents carbonyl, Y² represents lower alkylene that is unsubstitutedor substituted by phenyl and may be interrupted by one or twoiminocarbonyl groups, X⁴ represents oxygen and A², independently of A¹and A³, represents a radical of the formula Ib or Ic definedhereinbefore, R⁹ represents amino, R¹¹ represents hydroxy or a radicalof the formula Ie in which X⁵ represents the group NH, Y³ representslower alkylene which may be interrupted by one or two iminocarbonylgroups, X⁶ represents oxygen and A³, independently of A¹ and A²,represents a radical of the formula Ib or Ic defined hereinbefore, R¹²represents hydrogen, acetyl or the same radical as R¹³, and R¹³represents hydrogen, acetyl or, independently of R², a radical of theformula Ia as defined hereinbefore, and the use of pharmaceuticallyacceptable salts of these compounds.

The invention relates principally to k) the use of the above-mentionedcompounds of the formula I in which the radicals A¹, A² and A³ representa radical of the formula Ic, and the use of pharmaceutically acceptablesalts thereof.

The invention relates especially to 1) the use of the above-mentionedcompounds of the formula I that carry only one phorphoryl substituent,that is in the radical R¹¹ or R⁹, and the use of pharmaceuticallyacceptable salts thereof.

The invention relates most especially to m) the use of the compounds ofthe formula I mentioned above under i) or k) that contain as the sugarmoiety a derivative of D-glucose and that, in the case of asymmetricsubstitution, have at the C-R³ the (D)-configuration, at the C-R⁶ the(L)-configuration, and at the C-N-R⁸ the (D)-configuration, and thatcarry (only) one phorphoryl substituent, that is in the radical R⁹ orR¹¹, wherein, in this phorphoryl substituent of the formula Ie, theradical A³ represents a radical of the formula Ic, which is definedaccording to h) or j), and the use of pharmaceutically acceptable saltsthereof.

The invention relates preferably to the use of compounds of the formulaI that have at an asymmetrically substituted C(-R³)-atom the(D)-configuration, at an asymmetrically substituted C(-R⁶)-atom the(L)-configuration, and at the C(-N-R⁸)-atom the (D)-configuration, andin which the sugar moiety is derived from (D)-glucose, X¹ represents thegroup NH, X² represents oxygen, R¹, R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹² and R¹³each represents hydrogen, R² represents C₁₋₃ -alkyl or phenyl, R³represents hydrogen or C₁₋₃ -alkyl, R⁶ represents hydrogen, C₁₋₃ -alkyloptionally substituted by hydroxy, methoxy, mercapto, methylmercapto orby halogen, phenyl or phenylmethyl each optionally substituted byhydroxy, methoxy or halogen, or heterocyclyl or heterocyclylmethyl eachcontaining one or two aza atoms and having 5 ring members, or R⁵ and R⁶together represent trimethylene, one of the radicals R⁹ and R¹¹represents a radical of the formula Ie in which X⁵ represents the groupNH or oxygen, Y³ represents C₂₋₃ -alkylene or a radical of the formula##STR7## in which each of U² and U³, independently of the other,represents C₁₋₃ -alkylene that is unsubstituted or substituted by C₁₋₃-alkyl optionally substituted by hydroxy, lower alkoxy, mercapto or bylower alkylmercapto, or by phenyl or phenyl-lower alkyl each of which isoptionally substituted by hydroxy, methoxy or halogen, or byheterocyclyl or heterocyclyl-(C₁₋₃ -alkyl) each containing one or twoaza atoms and having 5 or 6 ring members, X⁶ represents oxygen, and A³represents a radical of the formula Ic in which R¹⁶ represents hydrogenand R¹⁷ represents a 1,2-dihydroxyethyl or 2-hydroxyethyl group in eachof which at least one of the hydroxy groups is esterified by analiphatic C₁₆₋₂₀ -carboxylic acid that is optionally singly or doublyunsaturated, or is etherified by an aliphatic C₁₂₋₁₈ -alcohol that isoptionally singly or doubly unsaturated, and the other of the radicalsR⁹ and R¹¹ represents hydroxy, lower alkoxy, amino, lower alkylamino oraminocarbonyl-lower alkylamino, and the use of pharmaceuticallyacceptable salts of such compounds.

The invention relates most preferably to the use of compounds of theformula I that have at an asymmetrically substituted C(-R³)-atom the(D)-configuration, at an asymmetrically substituted C(-R⁶)-atom the(L)-configuration and at the C(-N-R⁸)-atom the (D)-configuration, and inwhich the sugar moiety is derived from (D)-glucose, X¹ represents thegroup NH, X² represents oxygen, R¹, R⁴, R⁷, R⁸, R¹⁰, R¹² and R¹³ eachrepresents hydrogen, R² represents lower alkyl or phenyl, each of R³ andR⁵, independently of the other, represents hydrogen or methyl, R⁶represents C₁₋₄ -alkyl, R⁹ represents amino and R¹¹ represents a radicalof the formula ##STR8## in which r represents 0 or 1, U¹ represents aradical of the formula ##STR9## and each of R^(a) and R^(b),independently of the other, represents the acyl radical of an alkanoiccarboxylic acid having from 12 to 22 carbon atoms or of an unsubstitutedaliphatic carboxylic acid having from 12 to 22 carbon atoms andcontaining one or two double bonds, and the use of pharmaceuticallyacceptable salts of such compounds.

The invention relates above all to the use in accordance with theinvention of the following compounds: the sodium salt ofN-acetylmuramyl-L-alanyl-D-isoglutamine-2-(1,2-dipalmitoyl-sn-glycero-4-hydroxyphosphoryloxy)-ethylamide,the sodium salt ofN-acetyldesmethylmuramyl-L-alanyl-D-isoglutamine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide,the sodium salt ofN-acetyldesmethylmuramyl-L-alanyl-D-isoglutamine-2-(1-palmitoyl-2-oleoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide,the sodium salt ofN-acetyldesmethylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide,N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(3-palmitoyl-rac-glycero-1-hydroxyphosphoryloxy)-ethylamide,the sodium salt ofN-acetylmuramyl-L-α-aminobutyryl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide, the sodium salt ofN-benzoylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide,N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(tetradecyloxyhydroxyphosphoryloxy)-ethylamide,N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(hexadecyloxyhydroxyphosphoryloxy)-ethylamide,the sodium salt ofN-acetylmuramyl-L-α-aminobutyryl-D-isoglutaminyl-L-alanine-2-[(3R)-hydroxy-(2S)-palmitoylamino-4t-octadecenyloxyhydroxyphosphoryloxy]-ethylamide,the sodium salt ofN-acetylmuramyl-L-α-aminobutyryl-D-isoglutaminyl-L-alanine-2-[(3R)-hydroxy-(2S)-palmitoylaminooctadecyloxyhydroxyphosphoryloxy]-ethylamide,the sodium salt ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(cholest-5-en-3β-oxyhydroxyphosphoryloxy]-ethylamide,the sodium salt ofN-acetylmuramyl-L-O-{(N-[2-(1-palmitoyl-2-oleoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-succinamoyl)-glycyl}-seryl-D-isoglutamine, the sodium salt ofN-acetylnormuramyl-L-O-(1,2-dipalmitoyl-rac-glycero-3-hydroxyphosphoryl)-seryl-D-isoglutamine,the sodium salt ofN-acetyl-6-O-([1,2-dipalmitoyl-rac-glycero-3-hydroxyphosphoryloxy]-acetyl)-normuramyl-L-alanyl-D-isoglutamine,the sodium salt ofN-acetyl-6-O-(1,2-dipalmitoyl-rac-glycero-3-hydroxyphosphoryloxy)-normuramyl-L-alanyl-D-isoglutamine,the sodium salt ofN-{N-[2-(1,2-dipalmitoyl-sn-glycero)-3-hydroxyphosphoryloxy]-ethyl}-succinamoylmuramyl-L-alanyl-D-isoglutamine,the sodium salt ofN-acetyl-6-O-{N-[2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-succinamoyl}-muramyl-L-α-aminobutyryl-D-isoglutamine,the sodium salt ofN-acetylnormuramyl-L-O-{N-[2-tetradecyloxyhydroxyphosphoryloxy)-ethyl]-succinamoyl}-seryl-D-isoglutamine,the sodium salt ofN-acetylmuramyl-L-O-{[N-(1-palmitoyl-2-oleoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-succinamoyl-L-phenylalanyl}-seryl-D-isoglutamine,the sodium salt ofN-acetylmuramyl-L-O-(hexadecyloxyhydroxyphosphoryl)-seryl-D-isoglutamineand the sodium salt ofN-acetylmuramyl-L-O-(1,2-dipalmitoyl-3-sn-glycerohydroxyphosphoryl)-seryl-D-isoglutamine.

The invention relates especially to the use of the compounds of theformula I described in the Examples, and of the pharmaceuticallyacceptable salts thereof, and above all to the use ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide,especially the sodium salt of this compound, referred to hereinafter ascompound I.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows therapeutic effect of orally administered compound I(single dose on day 3) on a group of 10 mice infected intranasally withthe virus strain Influenza A/Victoria/3/75 (20 mice in the controlgroup).

FIG. 2 shows therapeutic effect of orally administered compound I(single dose on day 7) on a group of 30 mice infected intranasally withthe virus strain Influenza A/Texas/1/77 (20 mice in the control group).

FIG. 3 shows prophylactic effect of, in each case, 10 mg/kg (single doseon 7th day before infection) of intranasally administered compound I orcompound II on a group of 10 mice infected intranasally with theHerpesvirus hominis 1/TUP (20 mice in the control group).

FIG. 4 shows therapeutic effect of orally administered compound I onguinea pigs infected with Herpes simplex Virus 2/Alabama. Statisticalsignificance *P≦0,05, **P≦0,01 (Vierfelder test).

FIG. 5 shows prophylactic effect of intranasally administered compound Ion guinea pigs infected with Herpes simplex Virus 2/MS. Statisticalsignificance *P≦0,005, **P≦0,01 (Vierfelder test).

FIG. 6 (FIG. 6a and FIG. 6b) shows therapeutic effect of orallyadministered compound I on mice infected with Parainfluenza Virus I(Sendai)/52. Statistical significance *P≦0,05, **P≦0,01 (Vierfeldertest). (FIG. 6a shows administration of active ingredient on 3rd dayafter infection and FIG. 6b shows administration of active ingredient on7th day after infection).

FIG. 7, Part I (FIG. 7a and FIG. 7b) shows effect of intranasallyadministered compound I on mice infected with Parainfluenza Virus I(Sendai)/52. Statistical significance **P≦0,01 (Vierfelder test). (FIG.7a shows administration of active ingredient on 21st day beforeinfection and FIG. 7b shows administration of active ingredient on 14thday before infection).

FIG. 7, Part II (FIG. 7c and FIG. 7d) shows effect of intranasallyadministered compound I on mice infected with Parainfluenza Virus I(Sendai)/56. Statistical significance *P≦0,05, **P≦0,01 (Vierfeldertest). (FIG. 7c shows administration of active ingredient on 7th daybefore infection and FIG. 7d shows administration of active ingredienton 7the day after infection).

The following Examples illustrate the invention but do not limit theinvention in any way.

EXAMPLE 1

Groups of 30, 40 or 50 female MF-2f SPF mice each having a body weightof 14-16 g, or of 12-14 g in the case of tests with herpes simplex 1viruses, are infected intranasally, under light anaesthesia using amixture of equal parts of ether, ethanol and chloroform, with lethaldoses (approximately LD₈₀₋₉₀ ; number of plaque-forming units [PFU] seeTable 1) of the undermentioned virus strains in the form of 0.05 ml ineach case of a suspension of the viruses.

At the time indicated below (days) in relation to the day of infection,10 or 20 of these mice are administered once (single dose) thequantities indicated in Table 1 of the active ingredient, the sodiumsalt ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide(compound I), in 0.05 ml or 0.1 ml of phosphate-buffered salt solution(PBS) or in 0.2 ml of a 0.05% by weight solution of sodiumcarboxymethylcellulose in double-distilled water, by means ofintranasal, intravenous or oral administration respectively, in themanner indicated in Table 1.

The remainder of the above-mentioned mice, that is 20 or 30, serve asthe control, that is to say they either receive no treatment or aregiven a placebo.

The intranasal administration of compound I is effected under lightanaesthesia using a mixture of equal parts of diethyl ether, ethanol andchloroform.

                                      TABLE 1                                     __________________________________________________________________________                    Time of                                                                       administration                                                                          Percentage of mice surviving 20 days after                                    infection                                                     Mode of                                                                             [days]    in dependence on the quantity of active                                       ingredient [mg/kg]                                  Virus     adminis-                                                                            -: before infection                                                                     statistical significance .sup.x P ≦                                    0.05, .sup.xx P ≦ 0.01 (Vierfelder                                     test)                                               [PFU]     tration                                                                             +: after infection                                                                      500                                                                              100 20  10  1   0.1 0   control                  __________________________________________________________________________    Influenza A/                                                                            intravenous                                                                         -7            80.sup.xx                                                                             90.sup.xx                                                                         30     20                           Victoria/3/75   -5            80.sup.xx                                                                             80.sup.xx                                                                         30                                  (H3N2)          -1            80.sup.xx                                                                             80.sup.xx                                                                         70.sup.x                            (mouse-          0            90.sup.xx                                                                            100.sup.xx                                                                         70.sup.x                            adapted)        +1            90.sup.xx                                                                             70.sup.x                                                                          60                                  [2 × 10.sup.3 - 1 × 10.sup.4                                                intranasal                                                                          -14                   60  70.sup.(x)                                                                        80.sup.x                                                                         40                           PFU]            - 7                  100.sup.xx                                                                        100.sup.xx                                                                         80.sup.x                                  oral  +3         70.sup.xx                                                                        90.sup.xx                                                                         80.sup.xx      15                                           +7        100.sup.xx                                                                       100.sup.xx                                                                         70.sup.xx                                   Influenza A/                                                                            intravenous                                                                         -7            66.sup.x                                                                              40  40     10                           USSR/92/77      -2            60.sup.x                                                                              70.sup.xx                                                                         50.sup.x                            (H1N1)          -1            70.sup.x                                                                              70.sup.xx                                                                         50.sup.x                            (mouse-          0           100.sup.xx                                                                             80.sup.xx                                                                         60.sup.x                            adapted)        +1            90.sup.xx                                                                             90.sup.xx                                                                         60.sup.x                            [3 × 10.sup.2 - 1 × 10.sup.3                                                      +2            90.sup.xx                                                                             50.sup.xx                                                                         40                                  PFU]            +6            60.sup.x                                                                              60.sup.x                                                                          40                                  Influenza A/                                                                            intranasal                                                                          -7                    50.sup.xx                                                                         40.sup.x                                                                          30.sup.(x)                                                                        0                           Texas/1/77 (H.sub.3 N.sub.2)                                                                  -7                   100.sup.xx                                                                         90.sup.x                                                                          70.sup.(x)                                                                       35                           (mouse-adapted)                                                                         oral  +7                    65.sup.xx   0                           [2 × 10.sup.0 - 1 × 10.sup.1                                      PFU]                                                                          __________________________________________________________________________                           Mode of                                                          Virus        adminis-                                                                            Application                                                                         Percentage survivors                                 [PFU]        tration                                                                             time  500                                                                              100                                                                              20 10 1  0.1                                                                              0                        __________________________________________________________________________              Influenza B/ intravenous                                                                         -7        90.sup.x                                                                            70                                                                               70   42                                 Hong Kong/5/72     -5        90.sup.x                                                                           100.sup.xx                                                                        80.sup.(x)                              [3 × 10.sup.5 - 1 × 10.sup.6 PFU]                                                    -2       100.sup.xx                                                                           90.sup.x                                                                        100.sup.xx                                                  -1       100.sup.xx                                                                           90.sup.x                                                                         80.sup.(x)                                                  0       100.sup.xx                                                                          100.sup.xx                                                                        90.sup.x                                                   +1        80.sup.(x)                                                                          80.sup.(x)                                                                       60                                                         +2       100.sup.xx                                                                           70                                                                               90.sup.x                                                   +6       100.sup.xx                                                                           80.sup.(x)                                                                       70                                                   intranasal                                                                          -7             100.sup.xx                                                                        80.sup.x                                                                         80.sup.x                                                                        30                                              oral  +3        50.sup.x                                                                               50.sup.x                                                                           15                                                    +7        80.sup.xx                                                                           90.sup.xx                                                                        50.sup.x                                Influenza B/ intranasal                                                                          -14             50.sup.x                                                                         20                                                                               20                                                                               0                                 Ann Arbor          -7              80.sup.xx                                                                        50.sup.x                                                                         20                                   (Ms.Lu.25.Russ)                                                                            oral  +3       100.sup.xx                                                                           90.sup.xx                                                                        80.sup.xx                                                                          15                                 (mouse-adapted)    +7       100.sup.xx                                                                           80.sup.xx                                                                        80.sup.xx                               [1 × 10.sup.1 PFU]                                                      Encephalomyo-                                                                              oral   0        80.sup.x                                                                           100.sup.xx                                                                        60   30                                 carditis           +2        60    80.sup.x                                                                         90.sup.xx                               [1 × 10.sup.1 - 1 × 10.sup.2 PFU]                                                    +4       100.sup.xx                                                                           70.sup.(x)                                                                       90.sup.xx                               Herpes Simplex                                                                             intranasal                                                                          -7              70.sup.x                                                                         60.sup.x                                                                         60.sup.x                                                                        20                                 1/TUP                                                                         [2 × 10.sup.4 PFU]                                                      Herpes Simplex                                                                             intranasal                                                                          -7              90.sup.x                                                                        100.sup.x                                                                         70                                                                              40                                 1/Virtue                                                                      [2 × 10.sup.3 PFU]                                            __________________________________________________________________________

The course of some of the above-described infections over a period oftime is illustrated in FIGS. 1 and 2.

The great superiority of the phosphoryl compounds of the formula I overmuramyl peptides, such as N-acetylmuramyl-L-alanyl-D-glutamine-n-butylester (compound II) is demonstrated, for example, by the fact that inthe case of the above-mentioned tests carried out for comparisonpurposes, on oral administration of 10 mg of the latter compound on day+7 all the mice die from infection with Influenza A/Texas/1/77, whilston administration of the same quantity of the phosphorylmuramyl peptidecompound I at the same time, as can be seen in the Table, 65% of themice survive the infection.

Furthermore, on intranasal administration of 1 mg/kg of compound II onday -7 it is not possible to detect any kind of protective action in thecase of infection with Influenza A/Texas/1/77, whilst on administrationof the same quantity of compound I at the same time 90% of the micesurvive the infection.

It is also not possible to detect any kind of protective action onintranasal administration of 10 mg/kg of compound II on day -7 in thecase of intranasal infection with Herpesvirus hominis 1/TUP, as can beseen from FIG. 3.

EXAMPLE 2

The number indicated in the following Table of female albino guinea pigsof the Pirbright strain (150-180 g body weight) are infectedintravaginally with ˜10⁴ PFU (plaque-forming units) of Herpesvirushominis 2/Angelotti, cultivated in HEL (human embryonal lungs) cells, asdescribed in B. Lukas et al., Arch. ges. Virusforsch. 44, 153-155(1974).

At the time indicated in the following Table (the time difference indays in relation to the day of infection, - [minus] indicating a timebefore infection) the number N of guinea pigs indicated in Table 2 aretreated intravaginally with a single dose of in each case 0.1 ml of agel containing the concentration of compound I indicated in Table 2.

The gel without active ingredient has the following composition:

    ______________________________________                                        2.25%         sodium carboxymethylcellulose                                                 (Hercules, USA)                                                 10%           glycerine                                                       made up to 100%                                                                             with bi-distilled water.                                        ______________________________________                                    

The effect of the treatment can be seen in Table 2.

The symptoms occurring in untreated animals are described in B. Lukas etal., Arch. Virol. 49, 1-11 (1975).

                                      TABLE 2                                     __________________________________________________________________________    Effect on local symptoms in the topical chemotherapy of Herpes genitalis      in guinea pigs                                                                (statistical significance .sup.x P < 0.05, .sup.xx P < 0.01 in the Fisher     test)                                                                         Active ingredient                                                                      Treatment                                                                             Animals [%] with regression of                               concentration                                                                          time    symptoms of ≧ 66% on day                                                              Symptom-free animals [%] on day               [%]      [days]                                                                              N 7  10  12  14  10 12  14 21  34                              __________________________________________________________________________    1.0      -7    14                                                                              29 79.sup.xx                                                                          71.sup.xx                                                                         93.sup.xx                                                                        21 57.sup.x                                                                          86.sup.xx                                                                         86.sup.x                                                                         100.sup.x                       0.1      -7    14                                                                              21 57.sup.x                                                                           86.sup.xx                                                                        100.sup.xx                                                                        43.sup.x                                                                         64.sup.xx                                                                         86.sup.xx                                                                         86.sup.xx                                                                        100.sup.xx                      1.0      +4    14                                                                              79.sup.xx                                                                        79.sup.xx                                                                          86.sup.xx                                                                         93.sup.xx                                                                        36 64.sup.xx                                                                         79.sup.xx                                                                         86.sup.xx                                                                        100.sup.xx                      0.1      +4    13                                                                              62.sup.xx                                                                        85.sup.xx                                                                         100.sup.xx                                                                         93.sup.xx                                                                        70.sup.xx                                                                        77.sup. xx                                                                        85.sup.xx                                                                        100.sup.xx                                                                        100.sup.xx                      0        +4    14                                                                               0  0   0   0   0  0   0  0   0                              (placebo)                                                                     control        20                                                                               0  0   0   0   0  0   0  0   20                             (untreated)                                                                   __________________________________________________________________________

EXAMPLE 3 Eye Drops

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I          0.10 mg                                                   boric acid          30.00 mg                                                  sodium tetraborate.10H.sub.2 O                                                                    0.10 mg                                                   benzalkonium chloride                                                                             0.20 mg                                                   water for injection to make up to 1.00 ml                                     ______________________________________                                    

Preparation

The boric acid, sodium tetraborate and benzalkonium chloride aredissolved while stirring at room temperature under aseptic conditions ina portion of the above-mentioned quantity of water for injection. CGP19835 is then dissolved in the resulting solution, and water forinjection is added to make up to the final volume of 1.0 ml.

The solution, or a portion or a multiple thereof, is filtered through amembrane filter and introduced into cleaned containers. Suitablecontainers are, for example:

flexible plastics containers (5 ml or 10 ml) having a droppingattachment,

glass containers (5 ml or 10 ml) having a glass or plastics droppingpipette and an elastomeric pipette filler, or

plastics single-dose pipettes (contents 1-2 drops).

EXAMPLE 4 Non-Aqueous Single Dose for Nasal Administration

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I       0.03 mg                                                      Miglyol 812      to make up to 30.00 mg                                       ______________________________________                                    

Preparation

0.03 mg of compound I is dissolved under aseptic conditions in 29.97 mgof Miglyol 812.

This solution is introduced into a commercially available single-dosenasal applicator, for example an applicator according to U.S. Pat. No.3,739,951, which is attached to an aerosol-container before use.

EXAMPLE 5 Nose Drops

    ______________________________________                                        Composition:    I          II                                                 ______________________________________                                        compound I      0.15 mg    0.10 mg                                            thiomersal      0.02 mg    --                                                 sodium monohydrogen                                                                           0.30 mg    0.30 mg                                            phosphate.2H.sub.2 O                                                          sodium dihydrogen                                                                             10.10 mg   10.10 mg                                           phosphate.12H.sub.2 O                                                         benzalkonium chloride                                                                         --         0.10 mg                                            disodium salt of                                                                              0.50 mg    0.50 mg                                            ethylenediaminetetra-                                                         acetic acid (EDTA)                                                            sodium chloride 3.70 mg    4.50 mg                                            demineralised water                                                                           988.30 mg  987.60 mg                                          pH value:       5.0 ± 0.3                                                                             5.0 ± 0.3                                       lowering of freezing                                                                          -0.51° C.                                                                         -0.56° C.                                   point Δt                                                                ______________________________________                                    

Preparation

While stirring at room temperature, the sodium dihydrogen phosphate,disodium monohydrogen phosphate, sodium chloride, thiomersal and thedisodium salt of EDTA are dissolved in a portion of the above-mentionedquantity of demineralised water.

Compound I is then dissolved in this solution and the whole issupplemented with the remaining demineralised water.

The solution, or a portion or a multiple thereof, is filtered through amembrane filter and introduced into cleaned containers.

Suitable containers are, for example:

a) glass or plastics containers (5 ml or 10 ml) having a glass orplastics pipette with an elastomeric pipette filler

b) compressible plastics bottles having a central tube and a plasticsspraying head

c) single-dose plastics containers (contents 2-3 drops), or

d) glass or plastics bottles that are provided with a standardisedpumpable dosing spray made of plastics (no propellant).

EXAMPLE 6 Gel

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I           0.01 g                                                   glycerine 85%        10.00 g                                                  methyl paraben       0.12 g                                                   propyl paraben       0.03 g                                                   sodium carboxymethylcellulose                                                                      2.50 g                                                   (high viscosity)                                                              demineralised water  87.34 g                                                  ______________________________________                                    

Preparation

The methyl paraben and propyl paraben are dissolved in a portion of thehot demineralised water. The sodium carboxymethylcellulose is thenincorporated into the resulting solution while stirring vigorously.While stirring, the glutinous product is allowed to swell. Aftercooling, the glycerine and a solution of the active ingredient, compoundI, in the remaining water are then added to this product.

EXAMPLE 7 Cream

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I            0.10 g                                                  sorbitan monostearate 0.60 g                                                  cetyl alcohol         3.00 g                                                  isopropyl palmitate   2.00 g                                                  methyl paraben        0.12 g                                                  paraffin oil, viscous 10.00 g                                                 PEG (20)-sorbitan monostearate                                                                      4.40 g                                                  propyl paraben        0.03 g                                                  70% solution of crystalline sorbitol                                                                6.00 g                                                  in demineralised water                                                        stearic acid          9.00 g                                                  demineralised water   64.67 g                                                 ______________________________________                                    

Preparation

The fatty phase, comprising sorbitan monostearate, cetyl alcohol,stearic acid, PEG (20)-sorbitan monostearate, isopropyl palmitate andparaffin oil, is melted. The methyl paraben and propyl paraben are thendissolved in a portion of the hot demineralised water. The sorbitolsolution is added to the aqueous phase. While stirring, the aqueousphase is then added at approximately 75° C. to the fatty phase. Thecream base is then allowed to cool while stirring. A solution of theactive ingredient, compound I, in the remaining water is then added tothe cream base at approximately 40° C.

EXAMPLE 8 Nasal ointment

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I         0.03 g                                                     paraffin oil, viscous                                                                           20.00 g                                                     white petroleum jelly                                                                           30.00 g                                                     wool fat, anhydrous                                                                             40.00 g                                                     demineralised water                                                                             19.97 g                                                     ______________________________________                                    

Preparation

The fatty phase, comprising paraffin oil, petroleum jelly and wool fat,is melted. The aqueous solution of the active ingredient is incorporatedinto the fatty phase at approximately 50° C.

EXAMPLE 9 Skin ointment

    ______________________________________                                        Composition                                                                   ______________________________________                                        compound I        0.25 g                                                      sorbitan sesquioleate                                                                           10.00 g                                                     white beeswax     5.00 g                                                      cetyl alcohol     2.50 g                                                      methyl paraben    0.15 g                                                      paraffin oil, viscous                                                                           20.00 g                                                     propyl paraben    0.02 g                                                      stearyl alcohol   2.50 g                                                      white petroleum jelly                                                                           40.00 g                                                     demineralised water                                                                             19.58 g                                                     ______________________________________                                    

Preparation

The fatty phase, comprising sorbitan sesquioleate, white beeswax, cetylalcohol, paraffin oil, stearyl alcohol and white petroleum jelly ismelted. The methyl paraben and propyl paraben are then dissolved in themain quantity of the water at elevated temperature. The aqueous phase isincorporated into the fatty phase at approximately 80° C. A solution ofthe active ingredient, compound I, in the remaining water is added tothe resulting ointment base at approximately 40° C.

EXAMPLE 10 Lipstick

    ______________________________________                                        Composition:                                                                  ______________________________________                                        compound I             1.00 g                                                 polyethylene glycol having an                                                                       15.00 g                                                 average molecular weight of 400                                               polyethylene glycol having an                                                                       83.00 g                                                 average molcular weight of 1000                                               polyethylene glycol having an                                                                        1.00 g                                                 average molecular weight of 4000                                              ______________________________________                                    

Preparation

The active ingredient is finely dispersed in the molten polyethyleneglycols. The viscous melt is poured into suitable lipstick cases andleft to harden.

EXAMPLE 11 Preparation of compound I

A solution of 1.5 mmol ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-N-hydroxysuccinimideester in 5 ml of dimethyl acetamide is added dropwise to a solution of 1mmol of 2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamineand 3.5 mmol of N-ethylmorpholine in 25 ml of chloroform:methanol:water=65:25:4. After stirring for 8 hours at room temperature the reaction iscomplete. 130 ml of water are added to the reaction mixture. Chloroformand portions of the methanol are distilled off under reduced pressure.The aqueous solution is filtered through a millipore filter made ofTeflon (pore size 5 μm). The filtrate is dialysed, while stirring, in anAmicon ultrafiltration cell through an Amicon YM 10 membrane (consistingof polysaccharide; nominal molecular weight cut off: 10 000 dalton) in adiafiltration process firstly against water (400 ml), then against 0.1Msodium phosphate buffer-0.1M NaCl, pH 7 (200 ml), and subsequentlyagainst water (850 ml). The internal dialysate is filtered through amillipore filter, pore size 0.45 μm, and freeze-dried, yielding thesodium salt ofN-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamidehydrate.

EXAMPLE 12

Groups of 20 female Tif:MF-2f (SPF) mice each having a body weight of14-16 g are infected intravenously, under light anaesthesia using amixture of equal parts of diethyl ether, ethanol and chloroform, with2×10³ PFU vaccinal virus IHD in the form of in each case 0.1 ml of asuspension of the virus in beef heart infusion broth.

10 of these mice from each of the above-mentioned groups are treated onthe fourth or sixth day after infection, that is to say on day +4 or +6(administration day), with a single oral administration of 1 mg/kg ofcompound I in 0.2 ml of a 0.05% by weight aqueous solution of sodiumcarboxymethylcellulose.

The remaining 10 mice from each of the above-mentioned groups serve asthe controls and receive a placebo.

On the seventh, ninth, tenth and twelfth day after infection the numberof tail lesions in the mice is determined, this being carried outsubstantially as described by J. J. Boyle, R. F. Haff and R. C. Stewartin Antimicrobial Agents and Chemotherapy, 536-539 (1967), and it shouldbe noted that the first tail lesions can be identified only on the sixthor seventh day. The results can be seen in Table 3:

                  TABLE 3                                                         ______________________________________                                                 Number of tail lesions (mean ±                                    Day of   standard deviation) on day                                           administration                                                                         +7        +9        +10     +12                                      ______________________________________                                        +4       0.9 ± 0.7*                                                                           0.9 ± 0.9*                                                                           0.9 ± 1.4*                                                                         0.2 ± 0.4*                            +6       1.1 ± 1.4*                                                                           0.9 ± 1.6*                                                                           0.3 ± 0.7*                                                                         0.5 ± 1.0*                            control  4.3 ± 1.9                                                                            4.3 ± 1.9                                                                            5.9 ± 1.9                                                                          4.6 ± 1.8                             ______________________________________                                         *statistical significance P ≦ 0.01 (Student's Ttest)              

EXAMPLE 13

Groups of 50-54 female albino guinea pigs of the Pirbright strain(150-180 g body weight) are infected intravaginally with 1×10³ PFU ofthe neurotropic virus strain Herpes simplex 2/MS in a manner analogousto Example 2. In the case of the Alabama strain, on the third day afterinfection 15 to 18 of these guinea pigs are administered orally a singledose, as indicated in FIG. 4, of compound I in 0.2 ml of a 0.005% byweight aqueous solution of sodium carboxymethylcellulose. In the case ofthe MS strain, on the seventh day before infection 17 to 19 of theabove-mentioned guinea pigs, under light anaesthesia using a mixture ofequal parts of diethyl ether, ethanol and chloroform, are administeredintranasally a single dose, as indicated in FIG. 5, of compound I in 0.2ml of a 0.005% by weight aqueous solution of sodiumcarboxymethylcellulose.

The control groups each comprise 35 animals and receive no treatment(FIG. 4) or are given a placebo (FIG. 5). The results are shown in FIGS.4 and 5, respectively.

EXAMPLE 14

Groups of 30 or 34 female Tif:MF 2f (SPF) mice each having a body weightof 14-16 g are infected intranasally under light anaesthesia with from10 to 50 PFU of Parainfluenza Virus 1 (Sendai)/52 (mouse-adapted, storedat -70° C. in the form of a mouse-lung suspension in ampoules). For theabove-mentioned anaesthesia there is used a mixture of equal parts ofdiethyl ether, alcohol and chloroform.

At the time indicated in FIGS. 6 and 7, 10 (in the case of FIG. 6) and14 (in the case of FIG. 7) of these mice are administered once thequantities indicated in the Figures of compound I in 0.2 ml of 0.005% byweight sodium carboxymethylcellulose in double-distilled water in themanner indicated in the Figures, in the case of intranasaladministration of the active ingredient before infection underanaesthesia using a mixture of equal parts of diethyl ether, alcohol andchloroform and in the case of intranasal administration of the activeingredient after infection under anaesthesia using Nembutal (0.5mg/mouse, intraperitoneal), followed after 20-25 minutes by intranasaladministration by drip of 0.02 ml of 1% aqueous cinchocainehydrochloride solution.

The remaining 20 mice from each of the above-mentioned groups serve asthe control. The control animals either receive no treatment or aregiven a placebo.

The action of compound I can be seen from FIGS. 6 and 7.

EXAMPLE 15

Groups of 30 female Tif:MF-2f (SPF) mice having a body weight of 14-16 gare infected intranasally under light anaesthesia, using a mixture ofequal parts by volume of diethyl ether, ethanol and chloroform, withlethal doses (approximately LD₈₀₋₉₀) of the virus strains indicated inTable 4. At the time shown in Table 4 [days in relation to the day ofinfection] 10 of these mice in each case are administered once (singledose) with the quantity, the active ingredient, and in the manner ofadministration, all as indicated in Table 4.

The active ingredients are:

the sodium salt ofN-acetyl-6-O-{[N-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethyl]-succinamoyl}-normuramyl-L-alanyl-D-isoglutamine(III), the sodium salt ofN-acetyl-1,4,6-O-triacetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide(IV), the sodium salt ofN-acetylmuramyl-L-alanyl-D-isoglutamine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide(V), and the sodium salt ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-γ-oxymethylcarbonyl-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamide(VI).

The remaining 20 mice in each group serve as the control, that is to sayinstead of the active ingredient they receive a placebo (0.005% byweight of sodium carboxymethylcellulose in double-distilled water).

The results of the test are shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________                                Percentage of mice surviving 23 days                                          after infection in dependence upon                                            the quantity of active ingredient                                   Mode of                                                                            Time of                                                                            [mg/kg]                                           Active            adminis-                                                                           adminis-           0                                   ingredient                                                                          Virus       tration                                                                            tration                                                                            100 10 1   0.1                                                                              (placebo)                           __________________________________________________________________________    III   Influenza A/Texas/1/77                                                                    oral +7       60 60  60 30                                        (H.sub.3 N.sub.2)                                                       III   Influenza A/Texas/1/77                                                                    intranasal                                                                         -7          50  40  5                                        (H.sub.3 N.sub.2)                                                       IV    Influenza A/Texas/1/77                                                                    oral +7       50 40     15                                        (H.sub.3 N.sub.2)                                                       V     Influenza A/Texas/1/77                                                                    oral +7   60  60 80     15                                        (H.sub.3 N.sub.2)                                                       VI    Influenza A/Texas/1/77                                                                    oral +7   60  40        15                                        (H.sub.3 N.sub.2)                                                       __________________________________________________________________________

EXAMPLE 16 Manufacture of 1000 tablets containing 0.5% of activeingredient

    ______________________________________                                        Composition for 1000 tablets:                                                 ______________________________________                                        compound I              0.5 g                                                 lactose, ground         43.0 g                                                corn starch             52.0 g                                                Pharmacoat 603  ® (hydroxypropyl-                                                                 3.0 g                                                 methylcellulose containing 28-30%                                             methoxy groups, supplied by Shinetsu                                          Chemical Company, Tokyo, Japan)                                               Aerosil ® (colloidal silica, supplied                                                             1.0 g                                                 by Degussa, Frankfurt, Federal Republic                                       of Germany)                                                                   magnesium stearate      0.5 g                                                 ______________________________________                                    

Preparation

Compound I and 15 g of lactose are premixed. The resulting premix ismixed with 28 g of lactose and 47 g of corn starch. Using the resultingmixture and an aqueous solution of the Pharmacoat a composition suitablefor granulation is prepared and is granulated, dried and ground. 5 g ofcorn starch, the Aerosil and magnesium stearate are mixed in and thewhole is pressed to form 1000 tablets each weighing 100 mg.

The compacts can be provided with a coating that is resistant to gastricjuices in a manner known per se.

EXAMPLE 17 Active ingredient in the form of a dry lyophilised substance

0.5 mg of compound I and 500 mg of mannitol (pyrogen-free) are dissolvedin water for injection and sterile-filtered through a membrane filter.The sterile-filtered solution is introduced under aseptic conditionsinto a sterilised glass ampoule or into a glass phial and freeze-dried.After lyophilisation the ampoule is sealed or the phial is sealed with arubber-elastomeric seal and aluminium cap.

EXAMPLE 18 Single-dose pipette with nose drops

A 0.05% solution of compound I in 1,2-propylene glycol, benzyl alcoholor ethanol or in a mixture of 1,2-propylene glycol and polyethyleneglycol having an average molecular weight of 300 is prepared.

The solution is filtered and introduced into single-dose pipettes madeof deformable plastics. The single-dose pipettes contain the quantity ofnose drops required for one application, that is to say they eachcontain 0.1 ml of the above solution.

We claim:
 1. A method of treating a viral disease due to a virusselected from the group consisting of Herpesviridae, Poxviridae,Picornaviridae, Orthomyxoviridae and Paramyxoviridae in a warm-bloodedanimal in need thereof comprising administering to said animal afterinfection an in-vivo anti-virally effective amount of a pharmaceuticallyacceptable salt of a compound which isN-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamidein the absence of a vaccine.
 2. The method of claim 1, wherein thesodium salt of said compound is administered as the sole activeingredient.
 3. The method of claim 1, wherein said salt is administeredin the form of a pharmaceutical composition containing a pharmaceuticalcarrier and less than 1% by weight of said salt.
 4. The method of claim1, wherein a single dose of not more than 10 mg of said salt isadministered once to a warm-blooded animal of approximately 70 kg bodyweight.
 5. The method of claim 4, wherein said dose is administeredabout 7 days after infection.
 6. The method of claim 1 wherein apharmaceutically acceptable salt ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamideis administered intranasally.
 7. The method of claim 1 wherein apharmaceutically acceptable salt ofN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamideis administered orally.
 8. The method of claim 1 wherein said viraldisease is due to a virus selected from the group consisting of Herpessimplex viruses belonging to Herpesviridae or Influenza A and InfluenzaB viruses belonging to Orthomyxoviridae.
 9. The method of claim 1wherein said viral disease is caused by a vaccinal virus belonging toPoxviridae, parainfluenza virus belonging to Paramyxoviridae orencephalomyocarditis virus belonging to Picornaviridae.